AFQ056, a new mGluR5 antagonist for treatment of fragile X syndrome

Neurobiol Dis. 2011 Jun;42(3):311-7. doi: 10.1016/j.nbd.2011.01.022. Epub 2011 Feb 21.


Fragile X syndrome, the most common form of inherited intellectual disability, is caused by a lack of FMRP, which is the product of the Fmr1 gene. FMRP is an RNA-binding protein and a component of RNA-granules found in the dendrites of neurons. At the synapse, FMRP is involved in regulation of translation of specific target mRNAs upon stimulation of mGluR5 receptors. In this study, we test the effects of a new mGluR5 antagonist (AFQ056) on the prepulse inhibition of startle response in mice. We show that Fmr1 KO mice have a deficit in inhibition of the startle response after a prepulse and that AFQ056 can rescue this phenotype. We also studied the effect of AFQ056 on cultured Fmr1 KO hippocampal neurons; untreated neurons showed elongated spines and treatment resulted in shortened spines. These results suggest that AFQ056 might be a potent mGluR5 antagonist to rescue various aspects of the fragile X phenotype.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Dendritic Spines / drug effects
  • Dendritic Spines / metabolism
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Mental Retardation Protein / metabolism
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Mice
  • Mice, Knockout
  • Neurons / drug effects*
  • Neurons / metabolism
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate / antagonists & inhibitors*
  • Reflex, Startle / drug effects*
  • Sensory Gating / drug effects*


  • Fmr1 protein, mouse
  • Grm5 protein, mouse
  • Receptor, Metabotropic Glutamate 5
  • Receptors, Metabotropic Glutamate
  • Fragile X Mental Retardation Protein